Severe Intestinal Failure Research Articles

Successful Long-Term Treatment of Collagenous Sprue With Tacrolimus in a 25-Year-Old With Severe Intestinal Failure.

Lay Summary A 25-year-old male presented with chronic watery diarrhea and severe intestinal failure due to collagenous sprue. Treatments, including immunosuppressants and a gluten-free diet, were ineffective. Tacrolimus shows promise in treating refractory cases.

ClinOleic Impairs ROS Production and Phagocytosis in M1 Macrophages Without Affecting M1 Differentiation.

Lipid emulsions are the primary source of calories and fatty acids that are used to provide essential energy and nutrients to patients suffering from severe intestinal failure and critical illness. However, their use has been linked to adverse effects on patient outcomes, notably affecting immune defenses and inflammatory responses. ClinOleic is a lipid emulsion containing a mixture of olive oil and soybean oil (80:20). The effect of ClinOleic on the differentiation of M1 macrophages remains unclear. In this study, we isolated human monocytes and added ClinOleic to differentiation culture media to investigate whether it affects monocyte polarization into M1 macrophages and macrophage functions, such as reactive oxygen species (ROS) production and phagocytosis. ROS production was stimulated by live S. aureus and detected with L-012, a chemiluminescence emission agent. Phagocytic capacity was assayed using pHrodo™ Green S. aureus Bioparticles® Conjugate. We found that M1 cell morphology, surface markers (CD80 and CD86), and M1-associated cytokines (TNF-α and IL-6) did not significantly change upon incubation with ClinOleic during M1 polarization. However, S. aureus-triggered ROS production was significantly lower in M1 macrophages differentiated with ClinOleic than in those not treated with ClinOleic. The inhibitory effect of ClinOleic on macrophage function also appeared in the phagocytosis assay. Taken together, these findings reveal that ClinOleic has a limited impact on the M1 differentiation phenotype but obviously reduces ROS production and phagocytosis.

Chronic severe intestinal failure associated liver disease is poorly defined by current criteria

Chronic severe intestinal failure associated liver disease is poorly defined by current criteria

90: Use of teduglutide during breast-feeding after pregnancy in a patient with severe intestinal failure

90: Use of teduglutide during breast-feeding after pregnancy in a patient with severe intestinal failure

104: Conversion from SMOFlipid® to Omegaven® as a Salvage Therapy for Severe Intestinal Failure Associated Liver Disease

104: Conversion from SMOFlipid® to Omegaven® as a Salvage Therapy for Severe Intestinal Failure Associated Liver Disease

High rate of venous thromboembolism in severe pediatric intestinal failure.

To quantify the rate of venous thromboembolism (VTE) in patients with pediatric intestinal failure and identify associated risk factors. We performed a retrospective cohort study in pediatric patients (<21years old) with severe pediatric intestinal failure (≥90 consecutive days of parenteral nutrition) secondary to short bowel syndrome who were treated from 2014 to 2021 at an interdisciplinary intestinal rehabilitation program. The primary outcome was the incidence of VTE. Multivariable regression was performed to identify independent clinical predictors of VTE. A total of 263 patients (59.7% male) met the criteria for inclusion. The cumulative incidence of VTE was 28.1%, with a rate of 0.32 VTEs per 1000 catheter-days. On univariate analysis, the number of catheter days, number of catheters, and history of central line-associated blood stream infection were associated with VTE. On multivariable logistic regression, a higher number of catheters was an independent risk factor for VTE (aOR, 1.17; 95% CI, 1.06-1.29). Additionally, earlier gestational age was a risk factor for VTE such that every week decrease in gestational age conferred a 9% increased risk of VTE (aOR, 1.09; 95% CI, 1.02-1.16). In this retrospective study, 28.1% of patients with severe pediatric intestinal failure developed VTE; the number of catheters and early gestational age were noted to be independent risk factors for VTE. This high incidence of VTE highlights the need to investigate VTE in pediatric intestinal failure prospectively, including the potential benefit of prophylactic anticoagulation.

The changing (remote) face of adult home parenteral nutrition patient support and monitoring

Severe Intestinal Failure (SIF) Teams care for complex and clinically vulnerable patients requiring home parenteral support (nutrition +/- Intravenous fluids) (HPS). All centres should offer patient telephone support and encourage patients to self-manage, with guidance on when to contact the team. Understand activity related to this HPN management will help define the clinical workforce resource required to support this group.

Erythrocyte fatty acid membrane composition in children on long-term parenteral nutrition enriched with ω-3 fatty acids

Composite lipid emulsions containing soybean oil (30%), medium-chain triglycerides (30%), olive oil (25%), and fish oil (15%) (SMOF) are now widely used. We aimed to evaluate the tolerance, the efficiency, and the erythrocyte fatty acid (FA) profile for children on long-term home parenteral nutrition (HPN) receiving a composite fish oil-based emulsion (FOLE). At baseline, children (n=46) with severe intestinal failure highly dependent on parenteral nutrition (PN) for ≥1 y were included in the study when they had received the composite FOLE for >6 mo. Out of this baseline group, only 25 children remained highly PN-dependent (SMOF1, n=25) and could be assessed a second time, 2.4 y later (SMOF2, n=25). An independent control group ("weaned off PN" group; n=24) included children who had been weaned off PN for >2 y (median: 4 y). RBC-FA composition was established by GC-MS. Growth parameters, plasma citrulline, conjugated bilirubin, FA profiles, and the Holman ratio (20:3ω-9/20:4ω-6) were compared between groups. No difference for growth parameters, citrulline, and bilirubin was observed between the SMOF groups after 2.4 y (0.2<P<0.8). The weaned-off group did not differ from the SMOF groups for growth parameters (0.2<P<0.4) but citrulline was higher (P<0.0001) and conjugated bilirubin lower (P<0.01). The composite FOLE induced higher proportions of EPA (20:5n-3) (8.4%±2.9%) and DHA (22:6n-3) (11.7%±2.2%) than what was observed in weaned-off children (0.8%±0.4% and 6.6%±2.3%, respectively) but lower proportions of arachidonic acid (20:4n-6). However, the Holman ratio did not vary between groups (P=0.9), whereas the PUFA concentrations varied widely. Long-term use of the composite FOLE was well tolerated in HPN-dependent children. The RBC-FA profile alterations were consistent with the ω-3 PUFA-enriched composition of this emulsion without evidence of essential FA deficiency.

Use of home parenteral nutrition in severely neurologically impaired children

ObjectiveTo review the outcome of children with severe neurological impairment (NI) and intestinal failure (IF) referred to our specialist multidisciplinary IF rehabilitation service and to discuss implications.DesignCase report series, descriptive...

PE-21: Assessment of Moderate and Severe Intestinal Failure Associated Liver Disease. Clinical, Analytical and Histological Correlation

PE-21: Assessment of Moderate and Severe Intestinal Failure Associated Liver Disease. Clinical, Analytical and Histological Correlation

Combined use of creatinine and cystatin C improves the detection of renal dysfunction in children undergoing home parenteral nutrition.

Renal dysfunction can complicate home parenteral nutrition (HPN). The aims were, in the context of pediatric HPN, to assess renal function using the measured glomerular filtration rate (mGFR), determine the most accurate formula(s) to estimate GFR, and identify possible underlying mechanisms of renal impairment. A retrospective study was performed in 2 centers. Patients receiving HPN and aged 2-16 years without medical history of nephropathy were included. GFR was measured using iohexol clearance. Estimated GFR (eGFR) was calculated using creatinine, cystatin C-based, and combined (eGFRcr+cyst ) Schwartz formulas. A total of 36 patients (18 females) were included; they received HPN for 8 (2-16) years. The primary digestive disease was short-bowel syndrome for 16 (44%) patients, gastrointestinal motility disorder for 10 (28%), or congenital diarrhea for 10 (28%). The median (range) mGFR was 99 (33-136) ml/min/1.73 m2 ; 9 (25%) patients had mildly decreased mGFR (<90 and ≥60 ml/min/1.73 m2 ), and 2 (6%) had mildly to severely decreased mGFR (<60 ml/min/1.73 m2 ). The eGFRcr+cyst formula was the most accurate and precise to estimate GFR. A significant negative correlation between mGFR and PN duration was found for patients receiving PN for 6-7/7 days (P = .008). Activation of the renin-angiotensin system was identified in 15 of 36 (42%) patients. Renal dysfunction was frequent and correlated with the duration of PN only for patients with the most severe intestinal failure. The use of eGFRcr+cyst improves its detection in these patients. Chronic dehydration may be an underlying mechanism.

Congenital Tufting Enteropathy: Biology, Pathogenesis and Mechanisms.

Congenital tufting enteropathy (CTE) is an autosomal recessive disease of infancy that causes severe intestinal failure with electrolyte imbalances and impaired growth. CTE is typically diagnosed by its characteristic histological features, including villous atrophy, crypt hyperplasia and focal epithelial tufts consisting of densely packed enterocytes. Mutations in the EPCAM and SPINT2 genes have been identified as the etiology for this disease. The significant morbidity and mortality and lack of direct treatments for CTE patients demand a better understanding of disease pathophysiology. Here, the latest knowledge of CTE biology is systematically reviewed, including clinical aspects, disease genetics, and research model systems. Particular focus is paid to the pathogenesis of CTE and predicted mechanisms of the disease as these would provide insight for future therapeutic options. The contribution of intestinal homeostasis, including the role of intestinal cell differentiation, defective enterocytes, disrupted barrier and cell–cell junction, and cell-matrix adhesion, is vividly described here (see Graphical ). Moreover, based on the known dynamics of EpCAM signaling, potential mechanistic pathways are highlighted that may contribute to the pathogenesis of CTE due to either loss of EpCAM function or EpCAM mutation. Although not fully elucidated, these pathways provide an improved understanding of this devastating disease.

Comparison between bioelectric impedance analysis and computed tomography for the measurement of muscle mass in patients with type 2 intestinal failure

Rationale: Direct measurement of body composition is a valuable clinical tool for detailed nutritional assessments, but there are no data on the relative merits of different assessment modalities in patients with acute severe (type 2) intestinal failure (IF). The primary objective of this study was to assess the agreement of multi-frequency bioelectrical impedance analysis (BIA) and computed tomography (CT) at the third lumbar vertebra (L3), for the measurement of muscle mass in type 2 IF. The secondary objective of the study was to identify the prevalence of low muscle mass in this patient cohort.

Evolution of renal function in patients with severe intestinal failure on home parenteral nutrition.

BackgroundKidney disease is a frequent but underestimated complication in patients suffering from intestinal failure (IF) treated by long-term home parenteral nutrition (HPN). The evolution in glomerular filtration rate (GFR) over time is poorly characterized. The current equations for estimating GFR have limited precision. No study has specifically investigated the reliability of recent creatinine-based estimated GFR (eGFR) equations in this population. The aim of this study was to evaluate the renal function decline under home parenteral nutrition (HPN) with a gold standard method and compare the performances of routinely used eGFR equations.MethodsForty patients with HPN and two or more GFR measurements were retrospectively studied. The renal function decline was calculated by the slope drawn between the successive measured GFRs (mGFRs). The performances of the Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, full age spectrum and revised Lund–Malmö equations were compared with reference methods (inulin or iohexol clearance).ResultsThe mean mGFR was 78 ± 28 mL/min/1.73 m2. The annual decline of mGFR was −1.9 mL/min/1.73 m2/year. No predisposing factor was identified to predict impairment in renal function. eGFR formulas grossly overestimated mGFR and had a low level of accuracy.ConclusionsPatients with IF are at significant risk for impaired renal function. In this population, the tested eGFR equations were inaccurate. However, monitoring kidney function with mGFR remains important in these patients, as their GFR regularly declines and no specific risk factor has yet been identified.

Small bowel transplant: state-of-the-art vascular and nonvascular imaging.

Small bowel transplant (SBT) is a surgical procedure that may be used in patients with pathology resulting in severe intestinal failure resistant to conventional forms of surgical and nonsurgical treatment. Intestinal failure is defined as the failure of enterocytes to absorb sufficient macronutrients, water, and/or electrolytes to sustain homeostasis and/or promote growth. With the advancement of surgical techniques and advancements in perioperative transplant management, SBT has become an increasingly common treatment for intestinal failure, with survival rates for SBT comparable to those for other solid organ transplants. This review provides background on SBT, its variations, and the associated preoperative and postoperative imaging studies with regard to surgical planning and anticipated complications. With the increasing use of SBT, radiologists will be expected to be familiar with the diagnostic studies and available endovascular interventions associated with this procedure.

Optimizing Patient Care and Flow in Severe Intestinal Failure

Optimizing Patient Care and Flow in Severe Intestinal Failure

Nod2 deficiency functionally impairs adaptation to short bowel syndrome via alterations of the epithelial barrier function.

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene mutations are a risk factor for Crohn's disease and also associated with worse outcome in short bowel syndrome (SBS) patients independent of the underlying disease. The aim of this study was to analyze the effect of Nod2 deficiency on barrier function and stool microbiome after extensive ileocecal resection in mice. Male C57BL6/J wild-type (WT) and Nod2-knockout (KO) mice underwent 40% ileocecal resection. Sham control mice received simple transection of the ileum. Clinical outcome was monitored daily. Barrier function was measured with Ussing chambers using FITC-4-kDa-Dextran flux, transmucosal electrical resistance, and dilution potentials. Immunofluorescence of claudin-2 was studied. Composition of the stool microbiome was assessed by 16S rRNA gene sequencing. Resected Nod2-KO mice had impaired clinical outcome compared with resected WT mice. This was accompanied by increased stool water contents and increased plasma aldosterone. Histomorphological adaptation was independent of Nod2. Barrier function studies revealed impaired sodium to chloride permeability and altered claudin-2 localization in the absence of Nod2. Resection induced decreases of bacterial diversity and a shift of bacteriodetes-to-firmicutes ratios. Ileum and cecum resection-induced increase in proteobacteria was absent in Nod2-deficient mice. Verrucomicrobia were temporarily increased in Nod2-KO mice. Nod2 deficiency functionally impairs adaptation to short bowel syndrome via a lesser increase of epithelial sodium pore permeability, altered epithelial barrier function, and the microbiome.NEW & NOTEWORTHYNOD2 gene mutations are associated with the development of severe short bowel syndrome and intestinal failure. The influence of Nod2 mutations on intestinal adaptation in experimental short bowel syndrome has not been studied yet. Here, we provide data that Nod2 deficiency worsens clinical outcome and functional adaptation under SBS conditions in mice, indicating that NOD2 is required for successful adaptation after ileocecal resection.

Enteroids expressing a disease-associated mutant of EpCAM are a model for congenital tufting enteropathy.

Congenital tufting enteropathy (CTE) is an autosomal recessive disease characterized by severe intestinal failure in infancy and mutations in the epithelial cell adhesion molecule (EPCAM) gene. Previous studies of CTE in mice expressing mutant EpCAM show neonatal lethality. Hence, to study the cellular, molecular, and physiological alterations that result from EpCAM mutation, a tamoxifen-inducible mutant EpCAM enteroid model has been generated. The presence of mutant EpCAM in the model was confirmed at both mRNA and protein levels. Immunofluorescence microscopy demonstrated the reduced expression of mutant EpCAM. Mutant enteroids had reduced budding potential as well as significantly decreased mRNA expression for epithelial lineage markers (Mucin 2, lysozyme, sucrase-isomaltase), proliferation marker Ki67, and secretory pathway transcription factors (Atoh1, Hnf1b). Significantly decreased numbers of Paneth and goblet cells were confirmed by staining. These findings were correlated with intestinal tissue from CTE patients and the mutant mice model that had significantly fewer Paneth and goblet cells than in healthy counterparts. FITC-dextran studies demonstrated significantly impaired barrier function in monolayers derived from mutant enteroids compared with control monolayers. In conclusion, we have established an ex vivo CTE model. The role of EpCAM in the budding potential, differentiation, and barrier function of enteroids is noted. Our study establishes new facets of EpCAM biology that will aid in understanding the pathophysiology of CTE and role of EpCAM in health and disease.NEW & NOTEWORTHY Here, we develop a novel ex vivo enteroid model for congenital tufting enteropathy (CTE) based on epithelial cell adhesion molecule (EPCAM) gene mutations found in patients. With this model we demonstrate the role of EpCAM in maintaining the functional homeostasis of the intestinal epithelium, including differentiation, proliferation, and barrier integrity. This study further establishes a new direction in EpCAM biology that will help in understanding the detailed pathophysiology of CTE and role of EpCAM.

P1.15: Paediatric domino liver transplant following multivisceral transplant (liver-inclusive) with splenic preservation – A case report

Introduction:A multivisceral transplant followed by domino implantation of the resected liver to another patient was first reported by Tzakis in 1999. Since then there has not been much development in this technique and its implications for both recipients. We present a paediatric multivisceral transplantation with native spleen preservation followed by the use of the recipient’s liver as a domino graft for another child. Patients and Methods:Multivisceral donor: 3 year old boy with hypoxic brain damage, blood group O+, weight 14kg. Multivisceral recipient: 7 year old boy, blood group A+, weight 24 kg, with severe intestinal failure (Neuropathic intestinal dysmotility). No enteral feed and 24-h PN, with persistent central line infections. Listed for multivisceral transplant seeking immunological advantage. At transplant, normal native liver (mild portal fibrosis at biopsy) preserved for domino transplant. Splenic artery and left gastric artery were preserved. Pancreas removed leaving splenic vein. Spleno-caval shunt performed preserving native spleen. Native liver perfused with UW solution and stored. Multiorgan graft implanted (liver, stomach, duodenum, pancreas, small bowel and right haemicolon). CIT: 10h. Domino liver recipient: 3 year old boy, blood group: A+, weight 12 kg, with cholestatic liver disease. Domino liver transplant (graft weight: 484 g, CIT: 10h, duct-to-duct anastomosis). Results:Multivisceral recipient had bowel obstruction (day 3 post-transplant) that required laparotomy. No acute cellular rejection and no serious infections post-operatively. Stoma reversed at 5 m. He remains on enteral feeding and PN support due to rapid bowel transit. The domino liver recipient had acute cellular rejection (day 8 post-transplant). Anastomotic biliary stricture corrected with biliary reconstruction (6 m post-transplant). Conclusion:A liver-inclusive intestinal transplant seems to give an immunological advantage to the recipient by decreasing rejection episodes but make them vulnerable to lethal infections (Wu & Cruz, 2018), which is maybe worsened by native splenectomy at transplantation. Preserving the native spleen may reduce the incidence of PTLD, GVHD and risk of infections. The above case could be a better option than a modified multivisceral transplantation and using the multivisceral recipient’s liver as a domino graft will decrease the impact on the donor pool. More cases are required to establish the advantages of these surgical techniques.

Noninvasive assessment of liver fibrosis in pediatric intestinal failure patients using liver stiffness measurement by Vibration-Controlled Transient Elastography

PurposeThe purpose of this study was to evaluate the diagnostic utility of noninvasive Vibration-Controlled Transient Elastography (VCTE) for assessing liver fibrosis in pediatric intestinal failure (PIF) patients. MethodsData from children with severe intestinal failure (≥90 days parenteral nutrition dependence) who underwent liver stiffness measurement (LSM), as measured by VCTE, at our institution between December 2015 and March 2018 were reviewed. LSM was compared to METAVIR fibrosis score (F0-F4) on liver biopsy performed within 1 year of VCTE. ResultsSeventy children underwent 75 LSM. Sixty-three patients (38% female) had at least one valid LSM, and 63% had a history of cholestasis (direct bilirubin ≥2 mg/dL). Median (IQR) age at first valid LSM was 4.5 years (2.6, 8.7). Sixteen patients had a liver biopsy. LSM differentiated between METAVIR F0-F1 (n = 6) and F2-F4 (n = 10) with an area under the receiver operating characteristic (AUROC) curve of 0.883 (95% CI: 0.686–0.999). The optimal cut-point derived to predict F2-F4 was an LSM ≥6 kPa (sensitivity 80%, specificity 100%). ConclusionLSM as determined by VCTE can distinguish mild (F0-F1) from moderate/severe (F2-F4) liver fibrosis in PIF. VCTE could allow for serial noninvasive monitoring of liver injury, potentially facilitating timely modifications to hepatoprotective management.Type of Study: Study of Diagnostic Test.Level of Evidence: II.